Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Fischer, TH; Eiringhaus, J; Dybkova, N; Saadatmand, A; Pabel, S; Weber, S; Wang, Y; Köhn, M; Tirilomis, T; Ljubojevic, S; Renner, A; Gummert, J; Maier, LS; Hasenfuß, G; El-Armouche, A; Sossalla, S.
Activation of protein phosphatase 1 by a selective phosphatase disrupting peptide reduces sarcoplasmic reticulum Ca2+ leak in human heart failure.
Eur J Heart Fail. 2018; 20(12):1673-1685
Doi: 10.1002/ejhf.1297
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- Co-Autor*innen der Med Uni Graz
- Holzer Senka
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- Abstract:
- Disruption of Ca2+ homeostasis is a key pathomechanism in heart failure. CaMKII-dependent hyperphosphorylation of ryanodine receptors in the sarcoplasmic reticulum (SR) increases the arrhythmogenic SR Ca2+ leak and depletes SR Ca2+ stores. The contribution of conversely acting serine/threonine phosphatases [protein phosphatase 1 (PP1) and 2A (PP2A)] is largely unknown. Human myocardium from three groups of patients was investigated: (i) healthy controls (non-failing, NF, n = 8), (ii) compensated hypertrophy (Hy, n = 16), and (iii) end-stage heart failure (HF, n = 52). Expression of PP1 was unchanged in Hy but greater in HF compared to NF while its endogenous inhibitor-1 (I-1) was markedly lower expressed in both compared to NF, suggesting increased total PP1 activity. In contrast, PP2A expression was lower in Hy and HF compared to NF. Ca2+ homeostasis was severely disturbed in HF compared to Hy signified by a higher SR Ca2+ leak, lower systolic Ca2+ transients as well as a decreased SR Ca2+ load. Inhibition of PP1/PP2A by okadaic acid increased SR Ca2+ load and systolic Ca2+ transients but severely aggravated diastolic SR Ca2+ leak and cellular arrhythmias in Hy. Conversely, selective activation of PP1 by a PP1-disrupting peptide (PDP3) in HF potently reduced SR Ca2+ leak as well as cellular arrhythmias and, importantly, did not compromise systolic Ca2+ release and SR Ca2+ load. This study is the first to functionally investigate the role of PP1/PP2A for Ca2+ homeostasis in diseased human myocardium. Our data indicate that a modulation of phosphatase activity potently impacts Ca2+ cycling properties. An activation of PP1 counteracts increased kinase activity in heart failure and successfully seals the arrhythmogenic SR Ca2+ leak. It may thus represent a promising future antiarrhythmic therapeutic approach. © 2018 The Authors. European Journal of Heart Failure © 2018 European Society of Cardiology.
- Find related publications in this database (using NLM MeSH Indexing)
- Aged -
- Blotting, Western -
- Calcium - metabolism
- Enzyme Activation -
- Female -
- Heart Failure - metabolism
- Heart Failure - pathology
- Humans -
- Male -
- Middle Aged -
- Myocardium - metabolism
- Myocardium - pathology
- Phosphorylation -
- Protein Phosphatase 1 - metabolism
- Sarcoplasmic Reticulum - metabolism
- Sarcoplasmic Reticulum - pathology
- Find related publications in this database (Keywords)
- Heart failure
- Ca2+ cycling
- Arrhythmia
- Diastolic Ca2+ leak
- Protein phosphatases